Myoglobin

Myoglobin is a small (17.8 kDa) oxygen binding haem protein found in cardiac and skeletal muscle. It is released early from damaged muscle, appears in blood within 1 to 3 hours of injury, peaks at 6 to 8 hours and is cleared by the kidney, returning to normal within 24 hours. Measured by immunoassay in serum or plasma and, for rhabdomyolysis, in urine.

The early rise made it an attractive marker for myocardial infarction, but it lacks cardiac specificity and has been replaced by high sensitivity troponin. Its remaining uses are in the assessment of rhabdomyolysis and acute kidney injury from muscle breakdown, and as a negative predictor in some rapid assessments.

Rhabdomyolysis causes about 26 000 admissions a year in the United States, and acute kidney injury develops in 15 to 40% of them. Myoglobin is directly toxic to proximal tubules through iron release, casts and vasoconstriction. Myoglobinuria colours the urine reddish brown, but the urine dipstick shows blood without red cells, because myoglobin has peroxidase activity.

Indications. Suspected rhabdomyolysis (trauma, crush injury, prolonged immobility, seizures, exertion, heat stroke, drugs, toxins, infection, metabolic myopathy). Dark urine with positive dipstick blood and no red cells. Unexplained acute kidney injury. Early assessment of chest pain where troponin is not available. Suspected malignant hyperthermia or neuroleptic malignant syndrome.

Specimen. Serum or heparin plasma, 1 mL. Urine spot sample, 5 to 10 mL. Samples are analysed within hours, or the serum is frozen. Stable for 24 hours at 2 to 8 °C.

Reference values (assay dependent).

• Serum myoglobin: men 28 to 72 microg/L, women 25 to 58 microg/L (older assays report under 70 to 90 microg/L).
• Urine myoglobin: under 5 microg/L (negative on qualitative assays).
• Cut off for rhabdomyolysis: serum over 1000 microg/L and urine detectable, with the diagnosis settled by creatine kinase.

Myocardial infarction.

• Sensitivity of myoglobin at presentation is 50 to 60%, rising to over 90% at 6 hours. Specificity is poor (70 to 80%), and a rise needs confirmation by troponin.
• A negative myoglobin at 6 hours or more after onset has a high negative predictive value (over 95%) for excluding infarction, but high sensitivity troponin does this better.
• A rising myoglobin with a delta change over 25% in 1 to 2 hours supports acute injury.

Rhabdomyolysis.

• Creatine kinase is the main diagnostic test, with a level over 5 times the upper limit (over 1000 U/L, often over 5000 to 10 000 U/L) defining rhabdomyolysis.
• Myoglobin rises earlier and falls earlier than creatine kinase (half life 2 to 3 hours versus 1.5 days), so a normal myoglobin on day 2 to 3 does not exclude recent rhabdomyolysis.
• Myoglobinuria appears when plasma myoglobin exceeds the renal threshold (about 0.5 to 1.5 mg/dL), and dark urine usually needs a creatine kinase over 15 000 to 100 000 U/L.
• Risk of acute kidney injury rises with creatine kinase over 5000 U/L, and with dehydration, acidosis, sepsis and nephrotoxins.

Differentiating causes of positive dipstick blood.

• Haematuria: red cells on microscopy, clear plasma.
• Haemoglobinuria: pink plasma, low haptoglobin, raised lactate dehydrogenase.
• Myoglobinuria: clear plasma, normal haptoglobin, markedly raised creatine kinase and myoglobin.

Associated findings in rhabdomyolysis. Hyperkalaemia, hyperphosphataemia, hypocalcaemia (early), hyperuricaemia, raised AST and ALT and LDH, metabolic acidosis, and later hypercalcaemia during recovery.

Critical values and findings needing immediate action.

• Creatine kinase over 5000 U/L or serum myoglobin over 1000 microg/L with dark urine: immediate high volume intravenous isotonic fluid resuscitation to maintain urine output at 200 to 300 mL/hour in adults.
• Potassium over 6.5 mmol/L, or ECG changes: emergency treatment of hyperkalaemia.
• Compartment syndrome (pain, tense swollen limb, paraesthesia): urgent surgical review.
• Oliguria or anuria with rising creatinine: nephrology involvement, renal replacement for refractory hyperkalaemia, acidosis or fluid overload.
• Hypocalcaemia with symptoms: calcium only if symptomatic or severe hyperkalaemia, because of later rebound hypercalcaemia.

Interferences and pitfalls.

• Myoglobin is not cardiac specific: skeletal muscle disease, exercise, trauma, intramuscular injection, renal failure (reduced clearance), shock and burns raise it.
• It clears rapidly, and a late sample may be normal despite significant injury.
• Renal impairment prolongs the half life and raises baseline values.
• Different assays give different values, and results are not interchangeable.
• Urine dipstick positive for blood without red cells is suggestive but not specific, since haemoglobin has the same reaction.
• Alkalinising urine with bicarbonate has limited evidence, and mannitol may add risk, so these are not routine.
• Contrast and nephrotoxic drugs should be avoided during myoglobinuria.
• Myoglobin should not be used alone to rule in or rule out myocardial infarction.

Special groups.

• Children: rhabdomyolysis follows viral myositis, trauma, and metabolic disorders (fatty acid oxidation defects, McArdle disease).
• Athletes and military recruits: exertional rhabdomyolysis, with heat, dehydration and sickle cell trait as risk factors.
• Older adults: long lie after a fall is a common cause, and kidney injury is common.
• Regions: crush injuries after earthquakes and conflict, and snake bite (sea snakes and some vipers) cause rhabdomyolysis.

Follow up tests. Creatine kinase, creatinine and urea, potassium, calcium, phosphate, uric acid, urinalysis, liver enzymes and lactate dehydrogenase, blood gas, coagulation screen (disseminated intravascular coagulation), toxicology screen, thyroid function, genetic testing for recurrent episodes, and muscle biopsy or metabolic testing in recurrent exertional rhabdomyolysis.